The Role of GPI-anchored PrPC in Mediating the Neurotoxic Effect of Scrapie Prions in Neurons

There are two central phenomena in prion disease: prion replication and prion neurotoxicity. Underlying them both is the conversion of a host-encoded ubiquitously expressed protein, prion protein (PrPC), into a partially-protease resistant isoform, PrPSc, which accumulates in the brain. PrPSc is associated with both pathology and infectivity. In the absence of PrPC, PrPSc cannot be generated and PrP-null mice do not propagate infectivity or develop pathology on infection with scrapie. However, while PrPC expression is fundamental to both prion infectivity and neurodegeneration, the uncoupling of these processes is a growing concept in the field. This dissociation is evident in subclinical states of prion infection, where PrPSc levels are high in the absence of disease, and in transgenic mice experiments, where, despite extra-neuronal PrPSc accumulation, even in very high amounts, there is no neurotoxicity. Both these models have further implications. Thus depleting PrPC from neurons (but not glia) of prion-infected mice prevents clinical disease, and detaching it from the surface of cells by removing its anchor does the same. The uncoupling toxicity and infectivity has implications for the nature of the neurotoxic species
these mouse models suggest that the site for the generation of this species is intra-neuronal. This review considers the role of neuronal surface-expressed PrPC in mediating toxicity in prion infection, and the dissociation of this from the deposition of PrPSc.